Proliferative diseases such as cancer are a leading cause of death for persons of certain age groups. Uncontrollable or abnormal cell replication is a common characteristic of cancers. Much research is performed in an attempt to determine a cause of cancer and other proliferative diseases. In addition, much effort has gone into determining ways to regulate or control cellular replication, and in particular, the mechanisms which inhibit cellular replication. A need exists to modulate, enhance or inhibit cell division and/or DNA replication.
Significant research has also been performed in the area of neurological diseases or conditions. Examples of such diseases or conditions are Parkinson""s disease, Alzheimer""s disease, multiple sclerosis, and patients with spinal cord injuries. Patients with neurological diseases or conditions do not have curative or effective treatment options. Scientists are attempting to determine the mechanisms controlling neural development and, in particular, ways to promote neural growth and regeneration. A need exists to promote neurogenesis or the ability to facilitate neural differentiation.
The invention relates to a protein, called Geminin, which inhibits DNA or cellular replication and promotes neural growth. The C-terminus of Geminin inhibits DNA replication and the N-terminus promotes neural growth, also referred to as neurogenesis. The Geminin protein comprises domains with specific functions. For example, the protein has a replication inhibitory domain which inhibits DNA replication. Within this replication inhibitory domain is a coiled-coil domain which is the site of protein-protein interaction. Geminin also has a domain which elicits neurogenesis. Another domain of the Geminin protein is the destruction box domain, which is responsible for degradation of the Geminin protein upon poly-ubiquitination.
Therefore, the invention encompasses the nucleic acid sequence and the encoded amino acid sequence of the entire Geminin protein, the N-terminal portion, the C-terminal portion, the replication inhibitory domain and the destruction box sequence. The invention also pertains to a nucleic acid sequence and the encoded amino acid sequence of the C-terminus or replication inhibitory domain with a mutated, deleted, or non-functional destruction box sequence. A mutated, deleted, or non-functional destruction box sequence causes a protein that is refractory to poly-ubiquitin mediated degradation.
The invention also relates to an antibody or antibody fragment which binds to a portion of the Geminin protein. An antibody can be a monoclonal or polyclonal antibody. The antibody can inhibit Geminin function or its interaction with other proteins.
The invention also pertains to a plasmid or vector comprising a nucleic acid sequence which encodes the Geminin protein or a portion thereof, as described herein. A cell or bacterial strain may also be transfected with the nucleic acid that encodes a Geminin protein or a portion thereof. Additionally, the invention relates to a fusion protein having an amino acid sequence of a Geminin protein or a portion thereof conjugated with a portion of an immunoglobulin or an antibody binding domain.
The invention includes methods for inhibiting or enhancing DNA replication in cells by administering a Geminin protein, an agonist or an antagonist thereof. Furthermore, the invention relates to methods for treating patients with proliferative diseases, including cancer, by administering the same.
The invention also includes methods for inhibiting or enhancing neural growth or neurogenesis in cells by administering the Geminin protein, agonists or antagonists thereof. Consequently, the invention also pertains to methods for treating patients with a neurological disease, disorder, or condition. Examples of such diseases, disorders, or conditions are Parkinson""s disease, Alzheimer""s disease, multiple sclerosis, and a patient with a spinal cord injury. Such a method embodies transfecting the nucleic acid which encodes at least a portion of the N-terminus of Geminin into embryonic ectodermal cells, maintaining the cells in conditions suitable for cell differentiation and/or cell division, and then transplanting these cells into the injured or affected neural area.